Iron overload conditions such as thalassemia and hemochromatosis result from the increased intestinal absorption of iron from inorganic iron and heme iron. Chelation therapy has been used with limited success, phlebotomy is usually required for severe iron overload. This can become problematic in patients whose iron overload is accompanied by anemia. In Northern European and the U.S., the majority of iron (2/3) that is utilized by the body is derived from heme iron in the diet, and not inorganic iron. Inhibition of iron uptake from heme would be critical to any attempt to prevent iron absorption. We have developed a model for iron absorption from heme in both tissue culture cells and in the rat. The heme is solubilized in a bile salt micelle. Both tissue culture cells and in vivo iron is absorbed and incorporated into cellular proteins. Certain soluble porphyrin analogs are capable of inhibiting the uptake of iron from heme. These inhibitors would be a major advance in the treatment of iron overload diseases. We propose to investigate the toxicity and effectiveness of the compounds already identified, and to explore additional analogs synthesized by Porphyrin Products. This is important since there are no inhibitors of heme absorption currently recognized. PROPOSED COMMERCIAL APPLICATIONS: Development of pharmacologic agent to treat iron overload conditions.